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Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets.
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2017 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 7, 458-468 p.Article in journal (Refereed) Published
Abstract [en]

Islet amyloid and beta cell death in type 2 diabetes are heterogeneous events, where some islets are affected early in the disease process, whereas others remain visibly unaffected. This study investigated the possibility that inter-islet functional and vascular differences may explain the propensity for amyloid accumulation in certain islets. Highly blood-perfused islets were identified by microspheres in human islet amyloid polypeptide expressing mice fed a high-fat diet for three or 10 months. These highly blood-perfused islets had better glucose-stimulated insulin secretion capacity than other islets and developed more amyloid deposits after 10 months of high-fat diet. Similarly, human islets with a superior release capacity formed more amyloid in high glucose culture than islets with a lower release capacity. The amyloid formation in mouse islets was associated with a higher amount of prohormone convertase 1/3 and with a decreased expression of its inhibitor proSAAS when compared to islets with less amyloid. In contrast, levels of prohormone convertase 2 and expression of its inhibitor neuroendocrine protein 7B2 were unaltered. A misbalance in prohormone convertase levels may interrupt the normal processing of islet amyloid polypeptide and induce amyloid formation. Preferential amyloid load in the most blood-perfused and functional islets may accelerate the progression of type 2 diabetes.

Place, publisher, year, edition, pages
2017. Vol. 6, no 7, 458-468 p.
Keyword [en]
blood flow, heterogeneity, islet amyloid, pancreatic islets
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-330801DOI: 10.1530/EC-17-0148PubMedID: 28790139OAI: oai:DiVA.org:uu-330801DiVA: diva2:1146832
Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
In thesis
1. The Impact of Pancreatic Islet Vascular Heterogeneity on Beta Cell Function and Disease
Open this publication in new window or tab >>The Impact of Pancreatic Islet Vascular Heterogeneity on Beta Cell Function and Disease
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes Mellitus is a group of complex and heterogeneous metabolic disorders characterized by hyperglycemia. Even though the condition has been extensively studied, its causes and complex pathologies are still not fully understood. The occurring damage to the pancreatic islets is strikingly heterogeneous. In type 1 diabetes, the insulin producing beta cells are all destroyed within some islets, and similarly in type 2 diabetes, some islets may be severely affected by amyloid. At the same time other islets, in the near vicinity of the ones that are affected by disease, may appear fully normal in both diseases. Little is known about this heterogeneity in susceptibility to disease between pancreatic islets. This thesis examines the physiological and pathophysiological characteristics of islet subpopulations.

Two subpopulations of islets were studied; one constituting highly vascularized islets with superior beta cell functionality, and one of low-oxygenated islets with low metabolic activity. The highly functional islets were found to be more susceptible to cellular stress both in vitro and in vivo, and developed more islet amyloid when metabolically challenged. Highly functional islets preferentially had a direct venous drainage, facilitating the distribution of islet hormones to the peripheral tissues. Further, these islets had an increased capacity for insulin secretion at low glucose levels, a response that was observed abolished in patients with recent onset type 1 diabetes.  The second investigated islet subpopulation, low-oxygenated islets, was found to be an over time stable subpopulation of islets with low vascular density and beta cell proliferation.

In summary, two subpopulations of islets can be identified in the pancreas based on dissimilarities in vascular support and blood flow. These subpopulations appear to have different physiological functions of importance for the maintenance of glucose homeostasis. However, they also seem to differ in vulnerability, and a preferential death of the highly functional islets may accelerate the progression of both type 1 and type 2 diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1374
Keyword
Pancreatic islets, heterogeneity, islet vascularity, blood flow, islet transplantation, islet amyloid, insulitis, type 1 diabetes, beta cell proliferation
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-330805 (URN)978-91-513-0089-4 (ISBN)
Public defence
2017-11-23, A1:107a, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2017-10-31 Created: 2017-10-04 Last updated: 2017-11-15

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